Device for reconstituting a therapeutic solution, suspension or dispersion

ABSTRACT

The invention relates to a syringe-type device for freshly preparing a solution, suspension or dispersion, for example injectable formulations, preferably according to a method for reconstitution in a vacuum. The device is shown in FIG.  1 . The invention also relates to a method for packing the fresh preparation of the solution, suspension or dispersion in a cylindrical reservoir that can be used in a single or multi-dose syringe provided for the same. This is a method for packing the preparation inside the cylindrical reservoir, which is closed on one side by an injection plunger whose movement in the reservoir is limited. This method is characterised in that the elements to be packed are introduced into the reservoir from the injection plunger side before the reservoir is closed by said plunger. Said reservoir is a tube or ampule which is closed on the other side in advance.

A subject of the present invention is a device for the extemporaneouspreparation of a solution, a suspension or a dispersion, for exampleinjectable formulations preferably according to a vacuum-basedreconstitution procedure called VAC (“Vacuum Automatic Control”) whichis the subject of the previous French Patent Application No. 96/06886. Asubject of the present invention is also a preparation and packagingprocess of said formulations in said devices according to which thereservoir of said devices containing the solid part of said formulationwill then be sealed on the piston side, preventing its injection or itsrelease after reconstitution.

According to the invention, the device is preferably used as a device inwhich a part of the formulation is vacuum-packed and another isconstituted by the liquid part of the final preparation, each of thembeing packed in a separate reservoir forming part of said device.

In therapeutic preparations and, by way of example, more particularly inthe case of injectable forms, it is sometimes useful, preferable or evenindispensable to separate the constituents. The device and the processwhich are a subject of the present invention are more particularlyuseful in the cases in which one part of said constituents is innon-liquid form and another in liquid form. In particular, they can beapplied to any lyophilizate of injectable solutions, to a powder or anyother vacuum-packed solid forms such that they can form, afterreconstitution, a liquid, a gel or an injectable paste-like form.

By way of example of a form illustrating the usefulness of thisinvention, without this being limitative with regard to other possibleapplications, we can take the injectable forms in which one part is indry or solid form and another constitutes the liquid injection vehicle.

More precisely, the solid part will in general contain the activeingredient and can be a lyophilized form and the injection vehicle canbe an aqueous preparation intended to hydrate the dry form beforeinjection. The aim is then to reconstitute a solution or a suspension oreven an injectable dispersion.

This type of injectable form is widespread and the reasons for whichthey are used rather than a mixed liquid form are well known.

In particular, problems of stability or compatibility of theconstituents in the liquid mixture can be mentioned. Although such aseparate solid-liquid packaging allows the improvement of certainpoints, such as for example the preservation of the formulation overtime at a temperature compatible with its transport and storage, thefact remains that it is an arrangement which poses numerous specificproblems associated in particular with the existence of two sub-systems.

The traditional solution for this type of preparation is to bottle thesolid or lyophilized form, which is hydrated at the time of use bytransfer from a syringe injecting the liquid medium by means of a needleinserted through the stopper of the bottle. Once hydrated, theformulation is generally recovered by the same needle in said syringe.This syringe can have been previously loaded with liquid- from anampoule or a first bottle or the syringe can be pre-filled with theliquid phase of the mixture.

This relatively complicated operation sets the constitutive elements ofthe formulation in motion several times and presents risks ofcontamination (or contact with the needle) both for the user and therecipient patient. The variability of the results and therefore of thetreatment administered remains not inconsiderable depending onimponderable parameters such as the suitability or practice of theoperator.

A certain number of technical solutions for the device have thereforebeen developed in an attempt to simplify this preparation and/or toreduce the risks.

Certain solutions remain fairly close to the standard procedure startingwith packaging in several elements and seeking only to reduce part ofthe risk or problem. This is in particular the case for technicalsolutions in which an intermediate element is added between the bottleand the syringe in order to simplify the injection and recovery of theliquid. For example, the Monovial® device from Becton Dickinson orVial-Mate® from Baxter can be mentioned.

Although this approach hardly simplifies the extemporaneous preparationand is not in the category of pre-filled packagings or syringes, it hasthe merit above all in the eyes of the pharmaceutical industry of notmodifying the primary bottling of the solid form, synonymous with afilling and treatment process which is fully validated and known, usingexisting equipment.

Of course, there are other more radically novel approaches to the devicefor simplifying this problem which in general involve a pre-filledpackaging or syringe. For example, there may be cited the use ofbi-compartmental syringes which are generally equipped with deviationsor a by-pass where the mobile separators which exist between the twoparts of the same reservoir can be deactivated. By way of example,Becton Dickinson's Hypack liqui-dry® syringes or Vetter's Lyoject®syringe can be mentioned. In this case, the mobile separator is a pistonwhich, at the moment of rehydration, will move vis-a-vis a deviationarranged in the wall of the syringe.

This elegant solution has the advantage of reducing the injectableelements to a single unitary device. In its basic version, this solutioncan pose risks of error or incorrect handling during the reconstitutionoperation; however, certain practised improvements can allow these risksto be considerably reduced.

The main drawback for the pharmaceutical industry of such a deviceremains associated with the packaging in one and the same reservoir oftwo constituents one of which is liquid and the other solid and which donot usually have at all the same method of treatment and/orsterilization above all when the solid is prepared by lyophilization.Another drawback in this case is associated with the size or volumeoccupied by the bi-compartmnental element in the lyophilizer which,given the portion of the reservoir then allowed for the liquid part, canbe twice as large as in separate reservoirs.

In addition to this, there is the stability risk associated with theproximity and possibility of contact between the two parts of thereservoir through the mobile separator or piston.

Faced with this problem, other approaches to the packaging in a singledevice have been attempted in which the packaging is, this time, carriedout in two truly separate reservoirs.

By way of example, in this regard, the patent application PCT WO94/13344 (Meyer), can be mentioned, which describes a device in whichthe solvent or liquid is packed in a cartridge which can be standard andthe second part of the formulation (which can be a lyophilizate) iscontained in a straight specific tube with a sealed base.

There can also be mentioned Patent Application EP 298,595 whichdescribes a syringe constituted by several interlocking elementsincluding two reservoirs sealed before use, which can be connected via adouble-tipped needle.

The pistons called “obturators-pistons-valves” are characteristic and inparticular the tube piston which has grooves for a pre-positioning inlyophilization, also synonymous with dead volume.

The device is designed to be fully assembled, which means carrying outthis operation in aseptic conditions, or envisaging a joint liquid-solidpost-sterilization which risks being incompatible with one of the phasesor with the current thrust of certain directives. In this, this devicedoes not resolve the problem of unitary packaging, and thereforetreatment, of bi-compartmental devices.

In the light of the very broad industrial development of certainprocesses for filling around standard reservoirs or containers and theknown needs for aseptic preparation or customary post-sterilization, itwould be very desirable to be able, in this specific case of formulationin two sub-units, to have available a device which simplifies andsecures extemporaneous preparation whilst allowing the use of standardtreatments of existing reservoir sub-systems. This requirementpreferably involves the use of a prefilled device which avoidsproblematic transfers. For certain very fragile or sophisticatedproducts, it is important to avoid the agitation and movement created bythese transfers.

Another aspect of the problem associated with the operations of mixingthe two parts of the formulation then degassing (with risk ofcontamination depending on the extent and time of contact with theambient medium) explains the search for devices in which this mixing issimplified and, if possible, effected without prior opening to theoutside, even of devices in which degassing could be avoided.

The way in which the reconstitution is carried out and in particular itsspeed of realization and the losses associated with transfer anddegassing remain, whatever the device, random parameters which can leadto dissimilar results.

French patent application no. 96/06886 describes a process according towhich this reconstitution becomes automatic after actuation under theaction of the vacuum and in which the degassing operation is quitesimply omitted.

The applicant has now invented advantageous devices which satisfy all ofthese desiderata, for example in the form of an “in-syringe” arrangementvery close to that commonly known which allows the same therapeuticsteps to be preserved and the most standard reservoirs to be used. Thesedevices and these arrangements are characterized in that the non-liquidpart of the formulation to be injected is packed in the body of thesyringe and the liquid reconstitution part is packed separately in areservoir which can form the injection rod of the piston of the syringe.These arrangements are realized, in particular starting from standardreservoirs, by applying the preparation and packaging process whichconstitutes the other part of the invention and which consists offilling and sealing from the rear at the piston.

Similarly, the transfer system between the two parts is provided by aneedle, a tube or a rod which has the characteristic of entering thenon-liquid reservoir through the piston which will serve for theinjection of the reconstituted form.

These devices, according to the invention, moreover offer a means ofblocking said injection piston which allows the installation of saidtransfer system in said piston; said means of blocking can then bedeactivated, thus releasing said injection piston.

Finally, the device can include a mechanism by which, after entry intosaid piston, said transfer system is withdrawn before the injection inorder to restore the tightness of the reservoir containing theformulation to be injected.

This withdrawal will be, for example, according to the device detailedhereafter, combined with deblocking the injection piston.

A certain number of other more precise applications, derived orresulting from the devices according to the invention, will be specifiedin the more detailed descriptions which follow.

The devices and processes which are subjects of the present inventioncan advantageously operate using a reconstitution process which directlyallows an injection without prior degassing. Once reconstituted, theformulation can be used immediately at atmospheric pressure without riskof above- (or below-) atmospheric pressure; no risk, therefore, ofatomization or accidental squirting of the product at the moment itconnects with the injection needle. This, combined with the absence ofdegassing, eliminates significant concerns such as contamination oncontact with the environment and the risk of accidental pricks, theneedle no longer having to be handled in the open air before insertion.This needle can even be advantageously connected to the reconstitutedformulation only after it has been introduced into the body, whichallows the vein test to be carried out by simple sighting of the otherend of the needle after insertion.

One of the most standard reservoirs corresponding to the existingstandardization needs is the cartridge or injection cartridge, ending atone end in a standard piston and at the other in a sealed neck, aprotective cap or septum or a stopper and sealed by a metal cap.

Similarly, the devices according to the invention can advantageously usesuch standard cartridges for their two reservoirs as well as theexisting pistons and stoppers. The conditions for filling and sterilitytreatment for their two reservoirs can be exactly the same as thosegenerally applied to this type of container.

Thus the device according to the invention provides a novel and simplesolution which among other things answers the questions, problems andrequirements raised previously.

Moreover, the use of the vacuum-based automatic rehydration systemconstitutes per se a direct check on the integrity of the primary packcontaining the active ingredient, namely the reservoir or cartridge. ItsVAC operation offers a unique guarantee that the a sepsis of thereservoir has indeed been preserved during storage. This check can becombined with a secondary packaging under vacuum which will provide thesame check on the whole of the device and will optionally allow thevacuum check to continue for the duration of storage.

The descriptions which follow (general or more specific when based onthe figures) represent only a few advantageous examples of embodimentsof the device according to the invention, which can be implementedaccording to other specific versions also covered by the invention. Inaddition to a detailed possible device, certain other alternatives willtherefore be presented.

This device, according to the invention, can be applied, subject to afew minor modifications but still according to the same mechanicalprinciples, to numerous variations in the field of injectable materialand in other therapeutic fields. Certain specific details concerningthese other possible applications such as, for example, their use in apen-injector, will be given according to their relationship with theinventive matter.

In the example described and according to an advantageous embodiment ofthe invention, the device is presented with a total separation of thetwo reservoirs, namely that receiving the non-liquid elements (herelyophilizate) and that receiving the liquid elements (here suspendedaqueous medium). In other words, there is no physical link between thetwo reservoirs before use.

Said reservoirs can moreover advantageously be packaged separately andindividually. However, as will be specified, it is possible to envisagethe device in a pre-arrangement in which the two sub-systems arecombined or even included in the same pack.

The process aspect of the invention concerns the details of thepreparation and the packaging associated with the use of standardreservoirs and the use of the device, in particular around thelyophilizer.

Although the device of the invention could be realised with other typesof reservoir and in particular with glass tubes, in the advantageousembodiment of the device described in detail, two standard cartridges,for example with capacities of 2.25 and 3.15 ml, will be used asreservoirs.

The cartridge containing the non-liquid part, here the lyophilizate,constitutes the proximal reservoir situated inside said device anddirectly in contact with the outlet zone of the injection needle. It isin this proximal reservoir, which in general contains the activeingredient of the preparation, that the reconstitution takes place ofthe formulation to be injected, which is then, in terms of arrangement,in a mode equivalent to the traditional use of injection cartridges,exactly opposite the double-tipped needle.

The cartridge containing the liquid part or aqueous injection mediumconstitutes the distal reservoir of the device. It is situated at theother end of the injection device and also serves as the piston rodduring the injection of the preparation through the syringe which itforms with the assembly. It therefore penetrates to a greater or lesserdepth into the interior of the body of the syringe device and into theinterior of the proximal cartridge.

Located between these two cartridges are the various pieces or elementsof the connection mechanism which can be fixed on the piston of theproximal cartridge. The whole is preferably arranged inside a plasticbody which guides or controls certain of the functions and whichprotects the glass reservoirs.

The lower part of this exterior element which constitutes the body ofthe injection syringe which forms the device will preferentially have acylindrical shape, and its upper part will comprise the finger-rest ofsaid syringe. Each part can be a separate sub-element joined to theother at the moment of assembly. The lower part of this cylindrical bodycan also exercise a support and guiding function for the cartridge andthe injection piston during the lyophilization and vacuum-packagingoperations.

The proximal end of said lower part will support the injection needlewhich can be pre-fixed as represented below or, more conventionally,mounted on a base which will be attached to said proximal end.Advantageously, this end can therefore constitute a third externalelement fixed to the lower part.

The device is therefore presented below with a specific solution of aprefixed needle and screw-cap which avoids the risk of actuation beforereconstitution of the formulation. It is obviously possible to use thisdevice with any other needle and in particular non-pre-fixed needles,for example those of the standard type used on injectors or cartridgepens.

Similarly, for other applications (perfusion, ophthalmiatrics etc.), thedevice could be combined with a connector or transfer needle, adrip-feed or a spray.

On the distal side, the detailed solution keeps the liquid cartridge asa piston rod. In the case, for example, of a pen-injector, the whole ofthe body of the device can constitute the proximal part of the injectorand it is possible to envisage withdrawing the distal cartridge afterreconstitution and replacing it with the dosage mechanism of said pen,which would reseal the body of the device.

This solution is particularly advantageous given the precision of thetotal reconstituted dose and the small capacity of the pen-injector,without distal cartridge or bi-compartmental cartridge, which makespossible the use of the device according to the VAC procedure, thusallowing the case of a lyophilizate to be reduced to the simple andstandard case of a solution.

For reasons of clarity and logical sequencing of the operations in achronological order, after the general FIG. 1 of the detailed deviceaccording to the invention with the figures which follow, we willdescribe, in the first instance, the filling and packaging procedures(certain aspects of which constitute the second part, i.e. thepreparation process of the invention), before specifying the device ofthe invention which originated from it. These procedures correspond tothe assembly of the device of the invention which originated from it andallow said device and the functions of the elements which constitute itto be specified. We will finish, finally, in the figures, by describingthe use of said device.

The precise and specific device represented by the following figuresconstitutes only one possible solution embodying the device and theprocess according to the invention, which is in no case intended tolimit the general scope of said invention.

For example, the said lock elements represented hereafter could bereplaced by a key or side-pin system capable of blocking the piston ofthe vacuum-packed cartridge not only on its glass base but also on theplastic sleeve which surrounds it. Said key could be unlocked (orunpinned) after reconstitution according to the VAC procedure. Forreasons of convenience and space in the lyophilizer, said key systemcould be provided with a removable or independent handle or actuationgrip.

Similarly, although one of the advantages of the devices according tothe invention in terms of filling, sterilization and packaging, may bethe physical separation of the two reservoirs, it is perfectly possibleto assemble them in advance, either after sterilization (in asepticconditions), or before sterilization (with a post-sterilization of thewhole). In the case of the assembled solution, the liquid cartridge canbe provided with a blocking/deblocking device in the body of the syringewhich prevents its being accidentally handled. It can also ensure (forexample by a seal) the aseptic sealing of the body of the syringe.

In the solution represented by the figures, it is also possible toprovide a device or element which protects the membrane or the septum ofthe cartridge either of the flip-off type, or a system, for exampleretractable on the tube, which will protect this septum until theintroduction of the neck into the syringe body. Similarly, alongsidethis body and for example at the finger-rest, it is possible to providea means of protection, removable or piercable for example, which ensuresthat the transfer needle remains aseptic.

Finally, the device is presented in a pre-fixed needle solution. It ispossible to design the device according to the invention as simplyequipped with a stopper on the proximal side of the head of thecartridge; a stopper which will be withdrawn after reconstitution of themixture, and replaced by a needle the fitting of which by its base canensure the piercing of the membrane or stopper of the cartridge. Thispiercing can be carried out either by a double-tipped needle or by aplastic tip, an element of the base whose channel will be connected tothe needle. In order to specify the general part of the invention interms of the device and preparation and packaging process, following thedetailed example, other possibilities will be presented and theirtreatment process summarized.

One solution, adaptable to treatment in aseptic conditions and tosmaller volumes, will thus be mentioned. A simplified solution which isadaptable to small volumes and pen-injectors will also be described.Finally, an alternative solution to the detailed solution, in whichcertain automated aspects of the mechanism are dispensed with in favourof a general simplification. The specific process of the invention willbe stated each time.

FIGS. 1 TO 13

FIG. 1 represents a general view of the device of the invention afterinstallation of the piston rod formed by the liquid cartridge and beforeactuation.

FIGS. 2 and 3 represent schematically the standard filling processaround the standard cartridge containing the liquid phase, then itsspecific assembly so as to be capable of then being used in the deviceof the invention.

FIGS. 4 to 6 illustrate the packaging stages of the solid phase of theformulation in a standard cartridge and in the particular case of adispersion in a lyophilizate.

FIG. 7 represents the assembly stages of the proximal part of the devicearound the solid or lyophilized form.

FIGS. 8 and 9 describe, after the joining of the two sub-systems of thedevice (namely the body of the syringe containing the cartridge of solidmaterial and the rod of the syringe which is the cartridge for theliquid), the automatic VAC reconstitution and the operating mechanism ofthe device of the invention.

FIG. 10 represents the injection into the body of the fonnulationreconstituted in the device of the invention.

FIG. 11 represents an alternative device around another transfermechanism which can be used in aseptic conditions.

FIG. 12 illustrates a simplified device for small volumes and forpen-injectors.

Finally, FIG. 13 represents the application of the simplified device tothe case of the formulation and the volume of the previously detaileddevice.

DETAILED DESCRIPTION OF THE FIGURES

FIG. 1 represents a specific form of the device allowing the realizationof a medicinal solution or suspension, a solution of peptides orproteins for example, or an injectable suspension of PLGA microspheresallowing the sustained release of an active ingredient (delayed forms),according to the VAC process, from 2 basic reservoir elements, in thiscase cartridges. In particular, FIG. 1 represents this device beforereconstitution; once installed, the distal cartridge acts as a pistonrod and gives said device a very similar appearance to a standardsyringe. This version corresponds to the solution for 2 ml maximumvolume to be injected; the distal reservoir can be filled to a greateror lesser degree and determine the reconstituted volume.

This syringe device has a first container 11 constituted by thecartridge in which a solvent or aqueous medium 12 is stored, a secondcontainer 13 constituted by the cartridge in which the solid orlyophilizate form 14 is vacuum-packed, 4 transfer elements, namely theupper key 15, the lock 16, the lower key 17 and the transfer needle 18,and finally a sleeve 19 in which the reservoir 13 is located and whichmarks the point of entry at the distal end of the reservoir 11, servingas piston rod, and on which the injection needle 20 is fixed at theproximal end. It will be noted that the lyophilizate 14 whichcorresponds in the example to a suspension of microspheres (delayedform) can be replaced by any lyophilizate of injectable solutions, by apowder or any other vacuum-packed solid forms such that they can form,after reconstitution, a liquid, a gel or a paste-like form which can beused in said device.

The first container 11 serving as reservoir or distal cartridge andpiston rod of the syringe, is preferably stored and packed away from therest of the syringe, for example in an individual pack. All the rest ofthe device can advantageously be packed together in a second pack.

The cartridge 11 of the first container which contains the liquid medium12 is sealed at its two ends in a standard manner. At its proximal end,the sealing means will be for example a membrane or a sealing disk 21attached to the neck of the cartridge by a sealing cap 22 pierced in itscentre and which can, for example, be made from metal. This solution,equivalent to that used in dental cartridges among others, will inparticular allow filling by overflowing, preventing any bubbles of airinside the liquid. At its distal end, the cartridge 11 is sealed by apiston 23 which can be a standard injection piston, made for examplefrom rubber or polybromobutyl. This piston has an internal screw-thread24 where the piston rod is usually attached.

In the case of the device, this screw-thread 24 serves to attach, byscrewing, the short drainage rod 25 which will activate the rehydrationby “ unsticking”the piston 23 and will drain the transfer needle 18, byfilling it, after piercing the membrane 21. The length of said rod willdepend on the volume of the liquid in the cartridge 11. It will exceedsaid cartridge by a length which allows the piston 23 to be displaced bya distance at least sufficient for the displacement of the quantity ofliquid necessary for the drainage.

Moreover, this first container 11 also carries, attached to the distalglass end of the cartridge, a finger-rest 26. This finger-rest is thezone where the thumb comes to rest during the actuation orextemporaneous reconstitution operations. It can have the followingdifferent functions: it terminates the cartridge 11 like any syringe; inits function as piston rod of the device, it prevents cavities frombeing created by the displacement of the piston 23 while pressure isbeing exerted by the thumb, with the help for example of small openingsor escape passages situated under the support zone and communicatingwith the inside of the cartridge 11, behind the piston 23. It provides agrip during the unlocking of the second container 13, afterreconstitution due to a rearward movement of the assembly 11. Finally,the finger-rest 26 can serve to lock or block the piston 23 and itsdrainage rod 25 rearwards to prevent them from being extracted from thecartridge 11 or the drainage rod 25 from being unscrewed.

The second element of the device forming the body of the syringesurrounds the cartridge 13 containing the solid or lyophilized part 14of the vacuum-packed formulation. This cartridge 13 can also be sealedat its two ends in a standard manner. The proximal end, facing theinjection needle, can be blocked by a membrane or plug. According to anadvantageous embodiment which allows a standard lyophilizationtreatment, it will be sealed by a stopper 27 engaged in the neck of thecartridge. This stopper 27 can ensure a better tightness of the seal andthe maintenance of the vacuum in the cartridge 13; it will optionallyallow the reduction of the dead volumes of the injection cartridge;finally, it can be used like standard stoppers of bottles of lyophilizedforms, i.e. be pre-positioned after filling of the medium then freeingapertures or escape passages in order to eliminate the liquids, bysublimation during the lyophilization and can then stop the cartridgeunder vacuum in the lyophilizer using a customary mechanism. However,this standard possibility is not that described in the packaging processaccording to the invention.

This packaging process according to the invention constitutes a newadvantageous embodiment in that it allows the pre-sealing of thecartridge at its neck, for example with a standard membrane or plug,sealed by a metal ring, then the filling and lyophilizing of same fromthe rear before stopping it by its usual injection piston. Thus, thesealing elements are completely standard; operation is easy, from thelargest opening, and any dead volume is avoided.

The membrane or stopper 27 is sealed onto the neck by a cap 28 which canbe made of metal. The internal bevel of the injection needle 20 willconnect the formulation to the needle, through this membrane or thisstopper, at the moment of the injection.

At its other end, the container 13 is stopped by a piston 29 which canbe a standard cartridge piston made from rubber or polybromobutyl. Thispiston 29 has an internal screw-thread 30 or any other type ofattachment capable of attaching it firmly to a part of the lock 16forming the locking-unlocking mechanism with the keys 15 and 17. Here,for example, the base of the lock 16 is screwed onto the screw-thread ofthe piston 29. This lock 16 as well as the upper and lower keys arehollow, so as to contain, allow to circulate and monitor the movement ofthe transfer needle 18 during the actuation by transfer of the liquid.It is the cartridge 11 acting as piston which will activate the whole ofthis transfer mechanism with the part of its neck which will beconnected thereto. The lock 16 has, at its other end, support arms whichcome to rest on the glass base of the distal end of the cartridge 13 inlocking position. These bases prevent the pressure generated by thevacuum in the cartridge from carrying the piston downwards.

The lower key 17 surrounds the support arms of the lock. This key isfree in locked position. During the actuation, by introduction of theupper key 15, this lower key is firmly attached to the proximal part ofthe upper key. At this moment, the support arms of the lock 16 block theintroduction movement, permitting only a rearward movement withdrawingthe assembly comprised of cartridge 11 plus transfer elements.

During this withdrawal movement, the lower key 17 releases the lock 16by gripping the arms of the lock and blocking the transfer mechanismwhich then allows the injection.

The transfer needle 18 inside the transfer mechanism, and morespecifically the upper key 15, comprises a base 31 the role of which isto clip the needle 18 into the key 15 only after said needle is filledwith the liquid 12 and before the piston 29 is pierced.

For a totally reliable operation of the actuation, the length, thediameter and the type of bevel, on the cartridge side and piston side,can be optimized in such a way that the transfer needle systematicallypenetrates, firstly through the membrane 21 of the cartridge 11 and,only then, through the piston 29. For example, the needle can be fineron the cartridge side 11 with a long, more penetrating, bevel.

Similarly and according to the same objectives, and to guarantee moretightness during the penetration into the chamber under vacuum, themembrane 21 can be finer than the base of the piston 29. The latterpresents a thickness sufficient to guarantee the tightness during thepenetration of the needle 18 and, in particular, a thickness greaterthan the length of the bevel of this needle, on the piston side 29.

The rearward unlocking mechanism also allows, after VAC rehydration, thewithdrawal of the needle 18 from the piston 29. During the injection,the needle 18 remains blocked in the upper key 15 and the blocking ofthe mechanism by the withdrawal or clamping of the locking arms 16prevents said needle 18 from re-crossing the piston 29.

This assembly comprising cartridge plus transfer elements is containedin the case or sleeve 19 which forms the body of the syringe. Accordingto a preferred mode of arrangement of said sleeve, it is constituted bythree sub-systems locked or clipped into each other at the moment ofassembly.

The principal or central part of the sleeve 19 contains the cartridge 13Attached to its distal end is the end of the sleeve 32 which cancomprise the finger-rest part of the syringe or grip 33. Moreover, thisend can have the rearward locking and blocking mechanism of thecartridge 13 and of the transfer mechanism, thus preventing anywithdrawal after assembly.

The end or stopper of the sleeve 34 is attached to the proximal end ofthe central part 19. It is to this end that, in the version of FIG. 1,the injection needle 20 is attached at its base 35. The stopper or capprotecting the needle 36 can also be attached at the end 34.

This solution allows a device to be realized which is completelyequipped, in particular one with a pre-fixed injection needle withouthaving a problem with the length and the position of said needle duringthe packaging of the formulation.

In the version shown, this cap is blocked by a lock 37 held by the headof the cartridge 13. In this way, the cap 36 cannot be withdrawn nor thecartridge 13 connected to the injection needle 20 before the transfermechanism has been completely realized i.e. until withdrawal, after VAChydration.

The other specific functions of certain elements of the whole areexplained in the description of the figures which correspond to them.

An essential variant of FIG. 1, in the case of use for a multi-dosesystem of the pen-injector type, could be the attachment ofinterchangeable needles at the stopper end of the sleeve 34 which wouldthen seal the end of the pen-injector.

In this version, during the withdrawal after reactuation, the cartridge11 could be removed and replaced by a standard dosage and injectionmechanism which would be attached, by its container, to the sleeve 19 orto its end 32, for example, by screwing. This container of the dosageand injection mechanism would thus seal the pen-injector in its distalpart.

In the same way as the vacuum in the cartridges provides an integritycheck, the whole of the part of the body of the syringe of the devicecan be vacuum-packed and thus the same check performed, with a thermalisolation and a better stability or inertia as an advantage. This packvacuum can, for example, be greater than the vacuum in the cartridge 13to ensure the continuity, or double security, over the period ofstorage.

FIG. 2 represents schematically a standard filling procedure for thecartridge 11 containing the liquid part of the formulation. The piston23 is installed beforehand and its position in the tube of the cartridge11 precisely determines the liquid reconstitution volume. This liquidvolume 12 is added, according to a standard process which can berealized on automatic machines. The cartridge 11, once filled right upto the neck, is then sealed by a cartridge 22 containing for example amembrane 21, according to a method which is equally standard andautomatable. This process, which can be realized by overflow, preventsthe presence of gas inside the sealed cartridge.

FIG. 3 represents the insertion of the drainage rod 25 into thecartridge 11 for example by screwing onto the piston 23. The finger-rest26 is then attached or clipped onto the glass base of the cartridgetube. It can thus prevent any removal of the piston 23 and of the rod 25and prevent the disassembly of said rod 25. The thus-assembled whole canbe sterilized in a standard manner, for example, by autoclaving.

FIG. 4 represents schematically a comparison between a standardlyophilization bottle and the device according to the invention, whichconstitutes a part of the invention corresponding to the procedure oflyophilization and packaging at the rear or through the distal partopposite the proximal side of the injection and the neck of thecartridge. In a standard bottle A, the stopper 40 is pierced by holesand apertures which allow its positioning on the neck beforelyophilization and its sealing by pressure of the racks in thelyophilizer. The aim of the device according to the invention is toallow such a lyophilization, no longer with a standard bottle of type Abut with a standard cartridge 13 as shown in B. To do this, as weexplained previously, it is possible to use a stopper on the neck of thecartridge 13 equivalent, on a smaller scale, to the stopper 40 of thebottle A. In this case, the transfer mechanism where at least onelocking element attached to the piston 29 is pre-positioned at thedistal end of the tube of the cartridge 13 and the lyophilization iscarried out by opening the neck. This solution removes the lyophilizatefrom the heat-exchange tray and isolates it partially by the piston 29thus rendering the process more difficult. Moreover, it complicates thefilling by the narrow neck and does not allow a 100% filling.

In the solution of the process of the invention shown here, inparticular to optimize and facilitate the filling of the cartridge 13and to facilitate all operations for the preparation of thelyophilizate, the procedure is different. The cartridge is sealedbeforehand with its stopper 27 by a cap 28 (cf. FIG. 1); it is filledwith the preparation to be lyophilized through its large distal opening,up to the base of the neck. It is thus possible to use all standardcartridges in order to pack a lyophilized form there, even the smallestones, and also to operate all the possible arrangements of the futurelyophilizate, such as for example, the filling of two successive layerseither because they are incompatible or because the second serves toprevent the dead injection volumes. The injection piston 29 stops thecap at the end of lyophilization; unlike stopper 40, it is not equippedwith escape passages or openings synonymous with dead volume and it isnot pre-positioned on the glass base of the cartridge 13 but on acartridge support 19 in this reversed position which serves to guide it.This cartridge support can advantageously be the central part of thesleeve 19 or body of the syringe. The advantage is to have here aperfectly cylindrical shape which will maximize the saving of space inthe lyophilizer and the total filling of the useful volume of thecartridge 13. The sleeve 19 in its distal part has clip zones with thepart 32 of the body of the syringe which serve, here, both to hold thepiston 29 and the opening in the cartridge during lyophilization. Thepiston 29 is pre-fitted in this distal part of the sleeve 19 at leastwith a part of the transfer mechanism, namely, here, the lock 16 and thelower key 17. This guiding of the sleeve 19, once the device isassembled, serves here to block or stop the movement of the cartridge 13in the body of the syringe.

This reverse lyophilization therefore offers a whole range of advantageswhilst allowing a standard process with a good contact with the coldsource.

FIG. 5 illustrates the realisation of a specific packaging operation ofa formulation to be lyophilized carried out in a cartridge according toa process equivalent to that traditionally used with a bottle. In A, thecartridge 13 is washed and siliconized, in B, it is sealed by its capand membrane, in C, it can be fitted into a receptacle accommodating theshape of the bottle 40, in D and E, the constituents of the mixture areeasily introduced through the base, in F and G, all equivalenttreatments can be carried out with the bottle with the same guarantee ofheight to the outside. A treatment with ultrasound is representedschematically here. In the same manner, the mixture (vortex) or thesuspension could be stirred vigorously before freezing.

FIG. 6 shows a cartridge 13 filled with the mixture to be lyophilized,frozen beforehand or not. In A, this cartridge 13 is introduced into thesleeve 19 which serves as a support for it. In B, all the stages of thelyophilization cycle are usually carried out in the lyophilizer. In C,at the end of lyophilization, and still under vacuum, the piston 29 isintroduced inside the cartridge tube 13 by standard pressure in thelyophilizer on the lock 16. At this point, the lyophilizate iscompletely isolated from the outside by the sides of the piston 29 intight contact with the wall of the cartridge tube. In D, the vacuuminside the lyophilizer is broken, thus ensuring a return to atmosphericpressure. Under the action of this pressure, the piston 29 and the lock16 will continue to fall in the tube of the cap 19 thereby providing avisual and individual check on the existence and quality of the vacuumin the cartridge. This movement of the piston will be stopped by thesupport of the arm of the lock 16 on the cartridge 13. The sealedelement, thus constituted, then becomes an integral part of the deviceaccording to the invention.

FIG. 7 shows the sequence of the assembly operations for said device. InA, on the base of element D of FIG. 6, the other parts of the transfermechanism are assembled, namely the upper key 15 in which the transferneedle 18 is pre-fitted. This upper key can have a clip ring for thehead of the cartridge 11, higher around the needle to protect it duringhandling. In B, the proximal part or stopper of the sleeve 34 whichincludes beforehand the injection needle 20 and the cap 36 are attached,for example by clipping. In C, finally, the third part of the body ofthe syringe, namely the distal part of the sleeve 32, is attached. Thispart of the body of the syringe, can then be packed individually andpost-sterilized, for example by gamma-irradiation.

FIG. 8 shows the reconstitution stages of the formulation contained inthe device of the invention. In A, the cartridge 11 is introduced intothe body of the syringe. In B, the reconstitution is activated bypressure on the drainage rod 25. The first operation is therefore thepiercing of the disk 21 then the filling of the needle. In C, using thesame application of pressure to the rod, finally, the piercing of thepiston 29 is carried out. At this point, the movement is then blockedand the preparation is reconstituted automatically with the descent ofthe piston 23 in the tube of the cartridge 11.

FIG. 9 firstly shows, starting from stage C of FIG. 8, in A, theunblocking by removal of the piston rod constituted by the cartridge 11.This operation has already been described in the functioning of thetransfer mechanism. It pulls the cartridge 13 slightly to the rear asfar as its stop on the sleeve. In B, the removal of the cap, madepossible by the release of the cap 36 at its blockage 37, is carried outby slightly withdrawing the head of the injection cartridge 13. Only nowcan the injection cartridge 13 be connected to the injection needle 20.

FIG. 10 represents schematically the injection according to a completelystandard method. Given that the device according to the invention allowsa preparation which does not require drainage prior to injection, it ispossible, before A, to inject the needle 20 prior to its connection tothe cartridge 13. This stage can also serve as a direct vein test, forexample, in the case of IV or IM injection by sighting any return ofblood from the internal bevel of the needle before connection to theformulation. In B, at the end of the injection, the mechanism can beblocked to avoid any subsequent handling.

FIG. 11 represents another possible realization of the device accordingto the invention adaptable to treatments under aseptic conditions (inparticular for filling) and smaller volumes. The use of this device doesnot require any aseptic assembly after sealing into the lyophilizer, thedevice and its constitutive elements then being isolated from theoutside.

During the lyophilization process according to the invention thelyophilizate cartridge 13 is installed inside the sleeve 19 which isthen positioned in proximal position around the neck of the cartridgewhich it supports and which bears, at its distal end, the lock 16 sealedat one end by the piston 29 and at the other end by a film 15 with thetransfer needle 18 inside.

At the end of lyophilization, the reservoir is sealed by the piston 29by bearing on the lock 16 and with the help of the guide zones of thesleeve 19 (not shown). The device is then completely locked by the headof the sleeve 27 and the finger-rest 33.

The treatment of the liquid cartridge 11 is similar to the exampledetailed previously. At the moment of use, the cartridge 11 isintroduced through the film 41. It connects and drains the needle 18before piercing the piston 29 for the VAC rehydration.

Once this operation has been carried out, the lock 16 is unscrewed bybearing on the area of the sleeve 19 marked by the arrows, thus leadingto the rupture of the thin walls and the clipping of 2 arms which willretain the lock and curve the needle 18 then allowing its extractionfrom the piston 29. The injection needle can then be installed on thehead 27 and the injection carried out by the cartridge 11 serving aspiston rod 29.

FIG. 12 illustrates another representation of the device according tothe invention for the packaging of a solid form from the rear and itsrehydration process through the injection piston of the device.

Here, the lyophilization process from the rear, according to theinvention, is carried out on the cartridges 13 which have beenpreviously capped and installed in a lower support (not shown) indexedto the upper support (not shown) of the piston 29 and lock 16. At theend of lyophilization, the piston 29 and its lock 16 are introduced intothe cartridge 13. Another preferable solution according to the processof the invention consists of replacing these upper and lower indexedsupports by individual supports (21) for each cartridge. Theseindividual supports can then fulfil the role of receptacle as describedin FIG. 5. In addition, these supports can be directly used in thelyophilizer and can constitute the base of a pack realized with theupper individual support (22) of the piston 29 and of the lock 16.

After lyophilization, the individual lower (21) and upper (22) supportsclose to constitute, in the lyophilizer, the cartridge pack.

The liquid cartridge 11 is prepared as described previously; it can havea drainage rod but not necessarily a finger-rest. A sleeve 43 and apiston rod 42 can also form part of the device. Two injection needles 20(represented here in their cap) of the disposable needle type for apen-injector (for example Micro Fine® from Becton Dickinson) are alsonecessary for its use.

In the case of the use of this device as a single-dose syringe, thecartridge 11 is introduced into the sleeve 19 as represented in FIG. 12,a needle 20 is fixed and the rehydration is carried out by piercing thepiston 29 through the lock 16.

The sleeve 19 is then separated from the cartridge 11 and the lock 16 isunscrewed using the base of the needle 20 then placed in the cap. Thesleeve 19 can have lateral openings allowing the release of thecartridge 11 and its reuse for the injection of the preparationreconstituted in the cartridge 13 thanks to the addition of a piston rod42 to the piston 29 and the second needle 20.

In the case of the use of this device as cartridge of a multi-dosepen-injector, the cartridge 11 is introduced into the proximal part ofthe pen which could here be symbolized by the sleeve 19, a needle 20 isfixed to it and the rehydration and withdrawal of the lock 16 on thecartridge 13 are carried out as previously. The cartridge 13 thenreplaces the cartridge 11 in the proximal part of the pen for a standarduse of the latter as with the cartridges for products in solution.

FIG. 13 shows a simplified use of the device according to the inventionin the case of a formulation equivalent (in volume and composition) tothat of the detailed example. The device can therefore function with thesame cartridges 11 for the liquid part of the formulation 12 and 13 forthe lyophilized part 14 as those represented in FIG. 1.

The essential difference concerns the connector lock 16 which is screwedto the injection piston 29 and made in one piece. No assembly operationis necessary at this stage before sterilization. Similarly, it ispossible to avoid packaging before gamma irradiation.

The cartridge 13 is installed before lyophilization in the sleeve 19which will serve as a guide during sealing of the piston 29. The head ofthe syringe 34 constitutes the base of the needle 20. It can be fittedtight with the cap 36 on the sleeve 19 for example by means of an O-ringseal between the cartridge 13 and the sleeve 19.

In this case, no packaging is necessary and the device is closed betweenthe cap 36 and the connector lock 16. The finger-rest 33 can be clippedonto the distal part of the sleeve 19.

The use of this device, according to the invention, consists of fixing astandard needle 18 of the disposable-needle type for a pen-injector (forexample Micro Fine® from Becton Dickinson) onto the screw-thread of thesleeve containing the liquid cartridge 11 or, as represented here, ontothe single screw-thread 44 firmly fixed to the cartridge 11. Theassembly is then introduced into the connector lock 16 then through thepiston 29 by bearing on the drainage rod 25. After VAC rehydration, thecartridge 11 is withdrawn by unscrewing with the transfer needle 18 andthe lock 16; another solution consists of lengthening the arm retainingthe lock on the cartridge so as to clip the arms of the connector lock16 at that point, only after the needle has disappeared into said lock.The cartridge-connector lock assembly is then unscrewed from the piston29. A piston rod, which can be the cap 36, is fixed to the piston tocarry out the injection.

Principal Preferred Embodiments of the Invention

The invention therefore firstly relates to a device of syringe typeactuated by a piston in order to reconstitute a preparation, insolution, in suspension or in dispersion in a liquid inside a reservoirsealed by a piston and forming part of the body of said syringe,characterized in that the non-liquid part of said preparation is packedbeforehand inside said reservoir of said syringe and the liquid part ofsaid preparation is separated beforehand from said reservoir and saidsyringe, in which the reconstitution of said preparation is carried outby the transfer of said liquid part through said piston of saidreservoir.

According to preferred variants of the invention, said device canadditionally have at least one of the following complementarycharacteristics:

-   1) said liquid and said non-liquid are packed inside standard    injection reservoirs such as glass tubes or cartridges;-   2) said device includes characteristic 1) and is moreover a    single-dose or multi-dose syringe of the pen-injector type;-   3) the transfer during said reconstitution is carried out through a    tip, a duct, a tube or a hollow transfer needle introduced into said    piston;-   4) said piston has a blocking mechanism on said reservoir preventing    it being driven in before and during said reconstitution of said    preparation, which blocking mechanism can also optionally be the    connector of said liquid part on said reservoir of said syringe;-   5) said device has characteristic 4) described above and said    blocking mechanism is screwed onto said piston;-   6) said device has characteristic 4) or 5) and said blocking    mechanism can be deactivated, preferably after the reconstitution of    said preparation;-   7) said device has characteristic 6) and the deactuation of said    blocking mechanism also corresponds to the withdrawal of said    transfer needle from said piston;-   8) said liquid part is in a container which serves to actuate said    transfer into said reservoir of said syringe through said blocking    mechanism;-   9) said device has characteristic 8), said container then also    serving as injection rod to said piston;-   10) said device has characteristic 9), said standard reservoirs    being glass cartridges;-   11) said liquid is packed in a reservoir the piston of which is    actuated by a short rod allowing the displacement of said piston to    be initiated and said transfer element to be drained before    injection into said reservoir of said non-liquid;-   12) said device has characteristic 11), said reservoir of said    liquid being moreover equipped with an end preventing its blockage    by the thumb of the hand;-   13) said non-liquid part in said reservoir is vacuum-packed;-   14) said device has characteristic 13) said liquid part in said    second reservoir moreover automatically controlling, by its volume,    the reconstituted volume of said preparation;-   15) said device has characteristic 13) or characteristic 14), the    reconstitution of said preparation being operated automatically by    bearing on said second reservoir;-   16) said device, optionally having a characteristic or    characteristics chosen from among characteristics 1) to 15),    constitutes a single-dose injection syringe;-   17) said device, optionally having a characteristic or    characteristics chosen from among characteristics 1) to 14),    constitutes a multi-dose syringe of pen-injector type;-   18) said device has characteristic 17), said second reservoir being    withdrawn after said reconstitution and replaced by the dosage    mechanism;-   19) at least said reservoir of said device containing said    non-liquid part is then vacuum-packed;-   20) the injection needle is pre-fixed and its cap locked by a    locking mechanism before the reconstitution of said preparation.

According to a specific variant of the invention, the piston has ahollow transfer element and a blocking mechanism on the reservoir.Preferably, said blocking mechanism is hollow and contains said transferelement.

The transfer element can be for example, a needle, a point, a duct or atube. Preferably, it is a needle.

The invention also relates to a packaging process inside a cylindricalreservoir sealed at least on one side by an injection piston locked inits movement in said reservoir, characterized in that the elements to bepacked are introduced into the inside of said reservoir from saidinjection piston before said reservoir is sealed by said piston.

According to preferred variants of the invention, said process canadditionally have at least one of the following complementarycharacteristics:

-   a) said reservoir is a tube or a cartridge sealed beforehand on the    side opposite the piston;-   b) a lyophilization is carried out before sealing by said injection    piston;-   c) said cylindrical reservoir is introduced beforehand into a    support on which said piston is positioned beforehand, thus allowing    an opening to the outside of said reservoir through said support,    said piston then being introduced into said reservoir by pressure    and by displacement in said support which serves to guide it;-   d) said process has at least one of characteristics b) or c), said    piston being then definitively positioned in said reservoir by    ambient pressure thus allowing a packaging check;-   e) said process has characteristic c) or d), said support then being    an integral part of the final device;-   f) said elements to be packed are a mixture very vigorously stirred    beforehand in said reservoir;-   g) said process has one of characteristics b) to f), said elements    being introduced and frozen separately in a layer in said reservoir    before said lyophilization;-   h) said process optionally has a characteristic or characteristics    chosen from characteristics a) and b), said cylindrical reservoir    being introduced beforehand into a support and said piston locked in    another support, thus allowing an opening to the outside of said    reservoir between the two supports, said piston being then    introduced into said reservoir by pressure and by a bringing    together of said two supports;-   i) said process has characteristic h), said supports being moreover    hermetically closed after said bringing together and constituting    the package of said cylindrical reservoir.

All the variants disclosed previously represent only some of theembodiments made available to a person skilled in the art in the lightof the present description and cannot limit the scope of the presentinvention. The specialist will of course be able to adapt the teachinggiven to him here to his specific requirements.

1. A syringe type device actuated by a piston and intended toreconstitute a preparation, in solution, in suspension or in dispersionin a liquid, comprising: a cartridge constituting the proximal reservoir(13) containing the non-liquid part (14) of the preparation, saidcartridge (13) forming part of the body of said syringe and being sealedat one end by a fixed element (27) and at the other end by a piston(29); a cartridge constituting a distal reservoir (11) containing liquidpart (12) of the preparation, said cartridge forming an injection rod ofthe piston of the syringe; a hollow transfer element (18) locatedbetween the two cartridges (11, 13); and an injection needle (20);wherein these elements are all arranged inside a plastic body and thereis no physical link between the two said reservoirs (11, 13), saiddevice being characterized in that: a) said cartridge constituting theproximal reservoir (13) containing the non-liquid part (14) of thepreparation is under vacuum; b) said cartridge constituting the proximalreservoir (13) is directly in contact with the outlet of the injectionneedle (20); c) said piston (29) is prevented from being pushed in by alocking mechanism (16) on said reservoir (13), said locking mechanism(16) being able to be deactivated; d) said cartridges being designed sothat the cartridge constituting the distal reservoir (11) containing theliquid part (12) can penetrate into the interior of the body of thesyringe, and, provided the locking mechanism (16) is unlocked, into theinterior of the cartridge constituting the proximal reservoir (13)containing the non-liquid part (14) of the preparation; and e) thedevice includes a mechanism by which, after entry into said piston (29),said hollow transfer element (18) is withdrawn before the injection andthe tightness of the cartridge constituting the proximal reservoir (13)is thereby restored.
 2. A device of claim 1, wherein the lockingmechanism (16) is hollow and contains said transfer element (18).
 3. Adevice of claim 1, wherein deactivation of said locking mechanism (16)corresponds to the withdrawal of said transfer element (18) from saidpiston (29).
 4. A device of claim 1 wherein the transfer element is aneedle (18).
 5. A device of claim 1, wherein the said liquid part (12)is in a container (11) serving to activate said transfer into saidreservoir (13) of the syringe through said locking mechanism (16).
 6. Adevice according to claim 1, wherein said device is a single-dose ormulti-dose syringe of pen-injector type.
 7. A device claim 6, whereinthe liquid part (12) in the said second reservoir (11) in additionautomatically controls, by volume, the reconstituted volume of saidpreparation.
 8. A device of claim 6, wherein the reconstitution of thepreparation is carried out automatically by bearing on the secondreservoir (11).
 9. A device of claim 1,wherein the injection needle (20)is pre-fixed and its cap (36) locked by a locking mechanism (37) beforethe reconstitution of said preparation.